The solid-phase method introduced by Merrifield is now firmly established as a powerful technique for the study of biologically important peptides. Synthesis normally begins by covalently linking the C-terminal amino acid residue of the desired peptide to an insoluble polymeric support. This anchoring step is an integral part of the overall synthetic plan, and the experimental details can impact significantly on the overall purity and yield of the final product. Handles are defined as bifunctional spacers, or linkers, which serve to achieve the required attachment in two discrete chemical steps. The handle approach allows precise control over the stability and ultimate cleavage of the anchoring linkage, and facilitates quantitative attachments which circumvent problems associated with extraneous polymer-bound functional groups. Under the aegis of the present grant, a number of handles (PAL, HAL, XAL, NPE, Nonb, etc.) have been developed and applied to the stepwise or segment condensation synthesis of challenging peptide targets. Compatible N-alpha-amino protection is provided principally by acid-labile tert-butyloxycarbonyl (Boc) or base-labile 9-fluorenylmethyloxycarbonyl (Fmoc) functions, and final cleavages occur under relatively mild conditions with minimal side reactions upon exposure to acid, base, light, fluoride ion, or palladium (O) in the presence of nucleophiles. Depending on the experimental design, the products can be peptide acids or amides, either completely free or else retaining orthogonal side-chain protection. Some of the reagents and procedures developed in this research program have achieved widespread use throughout the world. The present renewal application aims to expand on this progress and continue to demonstrate how the aforementioned handles can help address biologically significant challenges in synthetic peptide chemistry. Simultaneously, modified and new chemistries are being examined that may lead to new handles with even better properties and/or a wider range of uses, including the preparation of peptide conjugates for tissue-targeted delivery. These methods will accommodate a range of scales, and be compatible with drug discovery programs and disease diagnosis procedures based on multiple peptide synthesis.